Background: Pressure injuries are a significant clinical and economic issue, affecting both patients and the health care system. Many pressure injuries in hospitals are facility acquired, and are largely preventable. Despite growing evidence and directives for pressure injury prevention, implementation of preventative strategies is suboptimal, and pressure injuries remain a serious problem in hospitals. Objectives: This study will test the effectiveness and cost-effectiveness of a patient-centred pressure injury prevention care bundle on the development of hospital acquired pressure injury in at-risk patients. Design: This is a multi-site, parallel group cluster randomised trial. The hospital is the unit of randomisation. Methods: Adult medical and surgical patients admitted to the study wards of eight hospitals who are (a) deemed to be at risk of pressure injury (i.e. have reduced mobility), (b) expected to stay in hospital for ≥48 h, (c) admitted to hospital in the past 36 h; and (d) able to provide informed consent will be eligible to participate. Consenting patients will receive either the pressure injury prevention care bundle or standard care. The care bundle contains three main messages: (1) keep moving; (2) look after your skin; and (3) eat a healthy diet. Nurses will receive education about the intervention. Patients will exit the study upon development of a pressure injury, hospital discharge or 28 days, whichever comes first; transfer to another hospital or transfer to critical care and mechanically ventilated. The primary outcome is incidence of hospital acquired pressure injury. Secondary outcomes are pressure injury stage, patient participation in care and health care costs. A health economic sub-study and a process evaluation will be undertaken alongside the trial. Data will be analysed at the cluster (hospital) and patient level. Estimates of hospital acquired pressure injury incidence in each group, group differences and 95% confidence interval and p values will be reported. Discussion: To our knowledge, this is the first trial of an intervention to incorporate a number of pressure injury prevention strategies into a care bundle focusing on patient participation and nurse–patient partnership. The results of this study will provide important information on the effectiveness and cost-effectiveness of this intervention in preventing pressure injuries in at-risk patients. If the results confirm the utility of the developed care bundle, it could have a significant impact on clinical practice worldwide.